Maxacalcitol, which has antiproliferative activity and differentiation activity to skin epidermal cells, has been widely used as an antipsoriatic agent and has received a high evaluation from medical experts in Japan.
Since maxacalcitol is chemically unstable and is readily decomposed in aqueous solutions, it has been believed that an oil-based ointment is a dosage form that can ensure chemical stability of maxacalcitol. Such a dosage form also exhibit high percutaneous absorption, and can be readily applied to trunks of bodies.
However, when an oil-based ointment containing maxacalcitol is applied to hairy areas of psoriasis, which disorder readily appears in not only trunks of bodies but also hairy areas such as heads, the ointment adheres to hair on the hairy areas. This causes a disadvantage in that a sufficient amount of maxacalcitol cannot be applied to affected sites of skin. Therefore, it is highly desired to provide a dosage form of maxacalcitol that can be readily applied to skin in the hairy area. A candidate of such a dosage form is lotion. However, a problem associated with using a lotion containing maxacalcitol is that a lotion generally exhibits percutaneous absorption inferior to that of ointment, and contains purified water which is responsible for the chemical unstableness of maxacalcitol. Further, although it is general that a solution-type lotion can be readily applied to skin compared with ointment, such a lotion readily gets into someone's eye due to dripping during application to his or her head.
WO99/29325 (Patent Document 1) discloses a solution-type lotion containing maxacalcitol and an ether surfactant. The ingredients of this lotion are adjusted such that maxacalcitol can be present in a chemically stable form, and an improvement in percutaneous absorption is expected for the lotion.
WO99/44617 (Patent Document 2) discloses an oil-in-water emulsion lotion that is free from intrusion into eyes due to dripping and that comprises tacalcitol (1α,24-dihydroxyvitamin D3) as an active ingredient, which is an activated vitamin D3 derivative like maxacalcitol; a solid oil component comprising white petrolatum and 0.2 to 1.00 higher alcohol; a liquid oil component comprising squalane; an aqueous phase component comprising ionic polysaccharide; and a nonionic surfactant having a HLB of 10 or above. Since tacalcitol was stable for a long time period in this oil-in-water emulsion lotion, it was anticipated that use of maxacalcitol as an active ingredient instead of tacalcitol was able to form a lotion chemically stable for a long time period. Experiments using maxacalcitol, however, do not show anticipated chemical stability. Furthermore, the percutaneous absorption of maxacalcitol was still unsatisfactory.
With respect to the chemical stability of maxacalcitol in an aqueous injectable solution, WO02/017932 (Patent Document 3) discloses that maxacalcitol is more chemically stable in the solution at a basic pH of about 8.0 than at a neutral pH. However, since a lotion is often exposed to air, stabilization achieved by such a basicity in the solution is not sufficient, and the basic preparation is significantly irritating to skin (Patent Document 1).
Accordingly, it is desired to provide a lotion that exhibits high percutaneous absorption and chemical stability of maxacalcitol, does not cause skin irritation, and exhibits less dripping from a head when it is applied to the head.
Patent Document 1: WO99/29325
Patent Document 2: WO99/44617
Patent Document 3: WO02/017932